Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib

“Platelet-derived growth factor receptor alpha (PDGFRA) is a target for tyrosine kinase inhibitors (TKIs)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese melanoma patients, and determined the inhibitory potency of TKIs such as imatinib and crenolanib on mutant PDGFRA. Experimental Design: 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14 and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays. Results: PDGFRA mutations were observed in 4.6% (16/351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations appear to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib. Conclusions: PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that melanoma patients harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment.”